Field of Invention
The present invention relates to sulfoxide compound and its application. More particularly, the present invention relates to method of producing benzothiophene derivatives from a sulfoxide compound having specific structure.
Description of Related Art
Benzothiophene derivatives are aromatic heterocyclic compounds, which are important intermediates of various pharmaceutical synthesis processes.
For example, raloxifene, which has been reported as one of unique selective estrogen receptor modulators (SERMs), is a benzothiophene derivative. SERMs show the function similar to estrogen on metabolism of skeleton and cholesterol. Moreover, SERMs also do antiestrogenic effect on breasts and endometrial hyperplasia. It is known that the mechanism of breast cancer arisen by estrogen is the combination of estrogen and receptor resulting in proliferation and differentiation of breast cancer cells. SERMs can make competition against the activation of estrogen receptor in breast cells. The main interaction between raloxifene, tissues and cells is first forming a complex by binding raloxifene to estrogen receptor, then the complex binds to various genes to initiate or inhibit the expression of genes. Thus, raloxifene and Tamoxifen, the first generation SERMs, can both reduce the incidence of invasive breast cancer. In addition, raloxifene can replace estrogen to increase bone mass density (BMD), improve osteoporosis, and lower concentrations of cholesterol and low-density lipoprotein in the blood. Therefore, processes of synthesizing benzothiophene derivatives have recently attracted great attention.
Some traditional methods of producing benzothiophene derivatives are described in U.S. Pat. No. 6,458,811, U.S. Pat. No. 4,133,814, U.S. Pat. No. 4,418,068 and U.S. Pat. No. 4,380,635, as shown in Reaction Scheme 1, all of which is incorporated herein by reference. Briefly speaking, in the traditional methods, 3-alkoxybenzenethiol [for example, the compound of formula (i)] and phenacyl bromide [for example, the compound of formula (ii)] firstly react in the presence of strong base to form aryl phenacylsulfide [for example, the compound of formula (iii)]. Next, aryl phenacylsulfide is heated to perform an intramolecular cyclization step in the presence of polyphosphoric acid (PPA), for forming 2-phenyl benzothiophene [for example, the compound of formula (iv)]. And then, the 2-phenyl benzothiophene and benzoyl chloride compound having different substituent groups [such as the compound of formula (v)] react to benzothiophene derivatives with benzoyl group [for example, the compound of formula (vi)] such as raloxifene of formula (vii) in Friedel-Crafts reaction.
However, in the traditional methods, the intramolecular cyclization tends to form two isomers of the benzothiophene derivatives, resulting in the decreased yield of the intermediates. Furthermore, the steps of the traditional methods are so complicated, which lead to poor synthesis efficiency.
Accordingly, it is necessary to provide a method of producing benzothiophene derivatives to prevent complicated reaction steps from decreasing synthesis efficiency of benzothiophene derivatives.
